Seventy to 85% of all people experience back pain at some time in life with direct costs of treatment being over $11.4 billion annually. Disorders of the intervertebral disc are commonly implicated in low back pain patients and are often associated with mechanical overloading. The outcome of the proposed work will be publications that develop a quantitative understanding of how healthy and damaging mechanical loading will influence intervertebral disc remodeling in vivo. We believe that understanding this remodeling response at the molecular level will provide a necessary foundation for development of a broad range of future treatment modalities including manual therapies as well as biological methods of tissue repair and replacement. The combined mechanical and biological aims are consistent with high priority funding topic areas defined at the 4th NIH/BECON Symposium 2001, Reparative Medicine: Growing Tissues and Organs. We first perform short-term 'screening' experiments to determine the effects of: 1) load duration and recovery time after load, and 2) torsional shear magnitude and frequency on the intervertebral disc cell anabolic and catabolic gene expression responses using a rat tail model. An external fixator will be surgically installed into the tail vertebrae of rats in vivo to allow precise mechanical control over the intervertebral joint loading conditions. Quantitative measurement of the relative mRNA expression of 8 important structural proteins and proteases will be made using real time RT-PCR. These initial screening tests will define those mechanical loading conditions that promote significant and specific alterations in mRNA expression that are anticipated to lead to changes in composition and structure. These short-term experiments are used to define a quantitative relationship between intervertebral joint loading and gene expression. The goal of Aim 3 is to perform a chronic study to evaluate how chronic mechanical loading leads to disc remodeling including the progression of disc degeneration. Intervertebral disc remodeling will be evaluated through measurement of composition, structure, and mechanical properties in addition to gene expression after 14 days and 56 days of continued loading. The chronic experiments will evaluate how changes in the message levels and enzyme activation/inhibition may lead to alterations in protein content and disc structure.